Post-Operative Pain (POP), also referred to as post-surgical pain, is a poorly understood syndrome following surgical procedures. POP is a complex response to tissue trauma during surgery that stimulates hypersensitivity of the central nervous system. The result is pain in areas not directly affected by the surgical procedure. Post-operative pain may be experienced by an inpatient or outpatient. It can be felt after any surgical procedure, whether it is minor dental surgery or a triple-bypass heart operation.
POP reduction is currently maintained by injecting short duration local anesthetics to the surgical wound, by the use of a local anesthetic delivery system (pumps) to the wound and by per os self-administration of pain relievers, mainly opiate based. It is desirable to prolong the effect and duration of the local anesthetics, thus to reduce the need for opiate-based analgesia post-surgery. Post-operative analgesic therapy with opiate based or NSAID can result in significant post-surgical complications, and may cause the patient to be substantially compromised with regards to gastrointestinal, respiratory, and cognitive functions.
Use of an extended release local anesthetic formulation can improve patients' well-being and expedite recovery, assist in patient compliance, reduce hospital stays and hospital costs and, therefore, result in cost savings to the patient and the healthcare system. The market for such extended release local anesthetics is expected to exceed several hundred million dollars annually in the U.S. alone.
There is a real need for providing different approaches to post-surgical pain management. A variety of interventions may be used before, during, and after surgery. Most of these methods involve medications given orally, intravenously, intramuscularly, or topically (via the skin). Some must be administered by a health care professional, others by self-administration by the patient.
Currently, post-surgical pain is managed by the administration of narcotics and analgesics immediately after surgery. These drugs are given by intravenous or intramuscular injection, or taken by mouth. Utilization of these drugs, nevertheless, has variant applications, while some hospitals insist on a routine of scheduled medications, other are giving medications only as needed.
Some hospitals advocate continuous, around-the-clock dosing via an injection pump-type dosing device that delivers medication into the veins (intravenously, the most common method), under the skin (subcutaneously), or between the dura mater and the backbone (epidurally). A health care provider programs the device for dosage and minimal intervals while delivery is controlled by the patient. Total permitted dosage during the time for which the device is set (commonly 8 hours, sometimes 12) is pre-programmed. The patient administers the dose by pushing a button, and is encouraged to keep a steady supply of medication within his or her system when pain increases. This is called patient-controlled analgesia (PCA).
PCA provides pain medication according to the patient's need. However, because opiate-like pain-relievers are the medications these pumps deliver, there has been some concern about possible narcotic addiction.
A useful method, by which long lasting post-operative analgesia can be achieved, is by a single application of a depot formulation. The depot can be optimized for injection, infiltration into an incision, implantation or topical application. In a depot formulation, a therapeutic agent is formulated with carriers providing a gradual release of the therapeutic agent over a period of several hours to several days, or longer. Depot formulations are generally based upon a biodegradable matrix which gradually undergoes degradation or disperses thus releasing the therapeutic agent.
Hence, the advantage of depot formulations is that active therapeutic agents are released gradually over long periods without the need for repeated dosing. These formulations are thus highly suitable for situations where patient compliance is difficult, unreliable or where a level dosage is highly important, such as with formulations of mood-altering active therapeutic agents, active therapeutic agents with a narrow therapeutic window, and active therapeutic agents administered to children or other patients whose lifestyle is incompatible with a reliable dosing regimen. Particular classes of active therapeutic agents for which this aspect offers an advantage include contraceptives, hormones (including contraceptive hormones, and hormones used in children such as growth hormone), antibiotics, anti-addictive agents, supplements such as vitamin or mineral supplements, anti-depressants, local anesthetics, pain relieving medications, and anticonvulsants.
Many depot formulations rely on particles incorporated into liposomes or microspheres for encapsulation of the therapeutic agent. Liposomal depot formulations, however, are difficult to manufacture, are extremely sensitive to surface active agents, have limited shelf-life or require a sub-ambient temperature for storage. Due to their particle size and fragile nature which prevents the use of common sterilization methods such as filtration, irradiation or autoclaving, liposomal multivesicular depot formulations are usually made under aseptic conditions which make the manufacturing process cumbersome and costly. In addition, liposomal depot formulations generally provide extended release of the therapeutic agent for up to 12 hours only. Various products are described with drugs incorporated into microspheres in oil based carriers. For example U.S. Pat. No. 6,132,766 to Sankaram et al. discloses a multivesicular liposome composition containing at least one acid other than a hydrohalic acid and at least one biologically active substance, the vesicles having defined size distribution, adjustable average size, internal chamber size and number, and provides a controlled release rate of the biologically active substance from the composition. The invention also discloses a process for making the composition which features addition of a non-hydrohalic acid effective to sustain and control the rate of release of an encapsulated biologically active substance from the vesicles at therapeutic levels in vivo.
US 2006/0078606 to Kim et al. provides a method for obtaining local anesthetics encapsulated in liposomes, such as multivesicular liposomes, with high encapsulation efficiency and slow release in vivo. When the encapsulated anesthetic is administered as a single intracutaneous dose, the duration of anesthesia and half-life of the drug at the local injection site is increased as compared to injection of unencapsulated anesthetic. The maximum tolerated dose of the encapsulated anesthetic is also markedly increased in the liposomal formulation over injection of unencapsulated anesthetic.
U.S. Pat. No. 7,547,452 to Atkins et al. provides sustained-release microparticle compositions. The microparticle composition can be formulated to provide extended release over a period of from about 7 days to about 200 days. The microparticles may be formulated with a biodegradable and biocompatible polymer, and an active agent, such as risperidone, 9-hydroxy-risperidone, and pharmaceutically acceptable acidic salts of the foregoing.
One local anesthetic formulation that has been used for short term post-surgical pain management is Naropin® Injection (ropivacaine hydrochloride monohydrate). Naropin® Injection is a sterile, isotonic solution that contains the enantiomer of bupivacaine, sodium chloride for isotonicity and water for injection. Sodium hydroxide and/or hydrochloric acid may be added for pH adjustment. Naropin® Injection is administered parenterally.
Naropin® Injection, however, has a relatively short duration of effect (4-6 hours). As a result, multiple repeated doses are typically required, forcing the patient to remain hospitalized during treatment or using a mechanical pump pre calibrated and patient operated to infiltrate the surgical wound with the analgesic drug as pain returns. Naropin® Injection has a maximum allowed dosage since it may affect the CNS and is contraindicated to be used IV. As Naropin® Injection is often combined with per os taken opiates when administered to treat post-operative pain; it retains some of the disadvantages associated with opiate-based analgesic therapy.
U.S. Pat. No. 5,863,549 to Tarantino is directed to a method for making in vivo a lecithin gel which provides for the sustained release of a biologically active compound contained in the gel. This invention is also directed to a method for the sustained treatment of a human or of other mammals with a therapeutic amount of a biologically active compound using the gel for the sustained release of the biologically active compound. The biologically active compounds disclosed and exemplified are peptides and polypeptides.
US 2005/0287180 to Chen provides compositions that comprise a phospholipid component (that contains one or more phospholipids) and a pharmaceutically acceptable fluid carrier, where the phospholipid component is in the range from about 10% to about 90% of the total weight. The compositions may further comprise non-phospholipid filler materials, where the amount of the non-phospholipid filler materials is in the range from about 5% to about 50% of the total weight. In certain embodiments, the compositions may be injectable, non-liposomal, and/or in form of a gel or a paste. The compositions of the invention may be useful for repairing and augmenting soft and/or hard tissues or for sustained local drug delivery. One drug formulation exemplified is bupivicaine in a phospholipid paste with propylene glycol.
US 2012/0046220 to Chen et al. provides a clear depot comprising at least one hydrophilic water-soluble pharmaceutically active antibacterial agent selected from the group consisting of vancomycin, gentamicin, a pharmaceutically acceptable salt thereof and a mixture thereof, water, a phospholipid, an oil, optionally a pH adjusting agent, and a viscosity modifying agent selected from the group consisting of ethanol, isopropanol, and a mixture thereof, wherein the water present in the final depot formulation is no more than about 4 wt % relative to the total weight of the depot and the depot has a pH of between about 3 and about 6.
US 2012/0316108 to Chen et al. is directed to compositions and methods of preparation of phospholipid depots that are injectable through a fine needle.
Additional references describing phospholipid-based formulations include WO 89/00077, WO 02/32395, EP 0282405 and U.S. Pat. Nos. 4,252,793; 5,660,854; 5,693,337 and Wang et al., Lyophilization Of Water-In-Oil Emulsions To Prepare Phospholipid-based Anhydrous Reverse Micelles For Oral Peptide Delivery, 39 European Journal of Pharmaceutical Sciences, at 373-79 (2010).
There is a need for prolonged post-surgical analgesia achieved by a single application at the end of the surgical procedure. The known phospholipid based depot formulations suffer from the drawback of high viscosity making them difficult to administer, and lack of long term stability at ambient temperatures. There is an unmet need for stable depot formulations of local anesthetics with improved viscosity making them amenable to delivery to the required site of action.